Up-regulation of cathepsin S expression by HSP90 and 5-HT7 receptor-dependent serotonin signaling correlates with triple negativity of human breast cancer

Gautam, Jaya; Bae, Young Kyung; Kim, Jung‐Ae

doi:10.1007/s10549-016-4027-1

Cited by 40 publications

(41 citation statements)

References 32 publications

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“…Such concurrent inhibition of both CTSS and MMP-9 further indicates that BJ-2302 might act on a common signaling molecule that is involved in the regulation of both CTSS and MMP-9 expression. Previous reports have shown that the PI3K/Akt and Ras/Raf/ERK pathways merged at NF-κB activation, which regulates CTSS and MMP-9 expression 14,41 . In MDA-MB-231 cells, BJ-2302 significantly suppressed nuclear translocation of NF-κB (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Based on previous reports that MMPs 33,34 and cathepsins 14,35–38 are highly expressed in breast tumors, we investigated the relative contribution of the proteases in breast cancer cell invasion and metastasis in multiple breast cancer cell lines. Unlike hormone-responsive breast cancer cells (MCF-7 and T47D), TNBC cells (MDA-MB-231, HCC-1973, and Hs578T) expressed higher levels of both MMP-2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have demonstrated the key role of different types of cathepsins in cancer cell invasion, such as cathepsin (CTS) B in glioma 10 , CTSL in ovarian carcinoma 11 , and CTSS in colorectal 12 and breast cancer metastasis 13 . Recently, elevated levels of CTSS in triple-negative breast tumor tissues have been demonstrated to play a critical role in MDA-MB-231 TNBC invasion 14 . In addition, CTSS has been suggested as a therapeutic target that does not induce any detrimental effects on MHC class II function, not only in cancer but also in the management of autoimmunity-related tissue-degrading diseases such as arthritis 15 .…”

Section: Introductionmentioning

confidence: 99%

“…A previous study has shown that CTSS expression in TNBC is regulated via dual signaling pathways, namely, PI3K/Akt and Ras/Raf/ERK 14 , leading to the activation of NF-κB, which is also a regulator of MMP-9. In addition, the PI3K/Akt and Ras/Raf/ERK pathways in TNBC cells are controlled by Src upon activation of both growth factor receptors (GFRs) and 5-HT 7 receptor 21 .…”

Section: Introductionmentioning

confidence: 99%

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Down-regulation of cathepsin S and matrix metalloproteinase-9 via Src, a non-receptor tyrosine kinase, suppresses triple-negative breast cancer growth and metastasis

et al. 2018

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Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer with poor prognosis. In the present study, we demonstrated that Src, a non-receptor tyrosine kinase, might provide an effective therapeutic strategy to overcome TNBC invasion and metastasis, which are mediated via the synergistic action of the lysosomal enzyme cathepsin S (CTSS) and gelatinase MMP-9. Knock-down of MMP-9 and CTSS using siRNAs resulted in a synergistic suppression of MDA-MB-231 cell invasion, which was similarly observed with pharmacological inhibitors. During the screening of new drug candidates that suppress both CTSS and MMP-9, BJ-2302, a novel 7-azaindolin-2-one derivative, was discovered. Src, an upstream activator of both pathways (PI3K/Akt and Ras/Raf/ERK) responsible for the expression of CTSS and MMP-9, was identified as a high-affinity target of BJ-2302 (IC90: 3.23 µM) through a Src kinase assay and a drug affinity responsive target stability (DARTS) assay. BJ-2302 effectively suppressed MDA-MB-231 cell invasion (Matrigel invasion assay) and metastasis (chorioallantoic membrane assay xenografted with MDA-MB-231-luc2-tdTomato cancer cells). Unlike Z-FL-COCHO (potent CTSS inhibitor), BJ-2302 did not induce any cytotoxicity in MCF-10A normal breast epithelial cells. Additionally, BJ-2302 (1 mg/kg) strongly suppressed TNBC cell proliferation in vitro and tumor growth in a xenograft mouse tumor model. The anti-metastatic and anti-tumor effects of BJ-2302 were superior to those of Z-FL-COCHO (1 mg/kg) or batimastat (30 mg/kg), a pan-MMP inhibitor. In summary, inhibition of Src kinase suppressed TNBC tumor growth and metastasis, and Src inhibitors such as BJ-2302 may constitute a novel therapeutic tool to treat breast cancer that expresses high levels of CTSS and MMP-9.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Down-regulation of cathepsin S and matrix metalloproteinase-9 via Src, a non-receptor tyrosine kinase, suppresses triple-negative breast cancer growth and metastasis

et al. 2018

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“…10 In addition to its wellestablished role in cognition, 11 circadian rhythms 12 and depression, 13 its involvement in various cancers has also been reported. [14][15][16][17][18] Although the 5-HT 7 receptor has been implicated in many lung-associated pathologic processes in rats 19,20 and guinea-pigs, 21,22 research on the 5-HT 7 receptor in human lungs is limited. 23 In our study, an exploration of mRNA expression using bioinformatics analysis and the results of immunohistochemistry analysis both showed higher 5-HT 7 receptor expression levels in the tumor tissues of NSCLC than in adjacent normal tissues, which indicates that the 5-HT 7 receptor may play a role in the progression of NSCLC.…”

Section: Introductionmentioning

confidence: 99%

<p>5-HT<sub>7</sub> Receptor Contributes to Proliferation, Migration and Invasion in NSCLC Cells</p>

Du¹,

Wang²,

Wang³

et al. 2020

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Introduction: Because only a small portion of NSCLC (non-small-cell lung cancer) patients benefit from molecular targeted therapy or immunotherapy and do not develop therapeutic resistance, continued research on new targets is warranted. Serotonin has recently emerged as a growth factor for tumor cells, and its receptors may be potential therapeutic targets. The mechanism related to the behavior of the 5-HT 7 receptor in NSCLC remains unknown. Methods: Both gene expression analysis and immunohistochemical analysis were conducted to evaluate 5-HT 7 receptor expression in NSCLC tissues. The correlation between 5-HT 7 receptor expression and clinicopathological features was also examined. Cell proliferation was measured using a CCK8 (Cell Counting Kit-8) assay and colony formation, migration and invasion were evaluated by the Transwell assay. siRNA transfection and stimulation with the selective agonist LP211 were used to identify the involvement of molecules in proliferation, migration and invasion. Quantitative real-time chain reaction (qRT-PCR) and Western blotting were used to quantifiy mRNA and protein levels, respectively. Pathway inhibitors facilitated the exploration of possible signaling pathways regulated by the 5-HT 7 receptor in migration and invasion. Results: The 5-HT 7 receptor was overexpressed in NSCLC tumor tissues compared with adjacent normal lung tissues. High 5-HT 7 receptor expression levels were correlated with lymph node metastasis (P=0.007) and advanced TNM stage (P=0.000) in NSCLC patients. The 5-HT 7 receptor positively regulated cell proliferation, migration and invasion in NSCLC cells. The stimulatory effect of the 5-HT 7 receptor on A549 cell migration and invasion may occur through the P38 pathway. In H1299 cells, the 5-HT 7 receptor might positively regulate Src to promote cell migration and invasion. Conclusion: Our findings suggest that the 5-HT 7 receptor, which mediates NSCLC progression, may be a potential therapeutic target.

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Cysteine Cathepsins in Breast Cancer: Promising Targets for Fluorescence-Guided Surgery

et al. 2022

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The majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after BCS, which necessitates re-resection or additional boost radiation. Cathepsin-targeted near-infrared fluorescence imaging during BCS could be used to detect residual cancer in the surgical cavity and guide additional resection, thereby preventing tumor-positive resection margins and associated mutilating treatments. The cysteine cathepsins are a family of proteases that play a major role in normal cellular physiology and neoplastic transformation. In breast cancer, the increased enzymatic activity and aberrant localization of many of the cysteine cathepsins drive tumor progression, proliferation, invasion, and metastasis. The upregulation of cysteine cathepsins in breast cancer cells indicates their potential as a target for intraoperative fluorescence imaging. This review provides a summary of the current knowledge on the role and expression of the most important cysteine cathepsins in breast cancer to better understand their potential as a target for fluorescence-guided surgery (FGS). In addition, it gives an overview of the cathepsin-targeted fluorescent probes that have been investigated preclinically and in breast cancer patients. The current review underscores that cysteine cathepsins are highly suitable molecular targets for FGS because of favorable expression and activity patterns in virtually all breast cancer subtypes. This is confirmed by cathepsin-targeted fluorescent probes that have been shown to facilitate in vivo breast cancer visualization and tumor resection in mouse models and breast cancer patients. These findings indicate that cathepsin-targeted FGS has potential to improve treatment outcomes in breast cancer patients.

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Up-regulation of cathepsin S expression by HSP90 and 5-HT7 receptor-dependent serotonin signaling correlates with triple negativity of human breast cancer

Abstract: Our findings suggest CTSS as a candidate target for development of a strategy to inhibit breast cancer invasion, and indicate that HSP90 and 5-HT (regulators of CTSS) should be considered as alternative targets for the management of TNBC invasion and metastasis.

Cited by 40 publications

References 32 publications

Down-regulation of cathepsin S and matrix metalloproteinase-9 via Src, a non-receptor tyrosine kinase, suppresses triple-negative breast cancer growth and metastasis

Down-regulation of cathepsin S and matrix metalloproteinase-9 via Src, a non-receptor tyrosine kinase, suppresses triple-negative breast cancer growth and metastasis

<p>5-HT<sub>7</sub> Receptor Contributes to Proliferation, Migration and Invasion in NSCLC Cells</p>

Cysteine Cathepsins in Breast Cancer: Promising Targets for Fluorescence-Guided Surgery

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